The present invention relates to large scale synthesis of twelve member diazamonocyclic compounds and to certain novel and useful compounds prepared thereby.
Lehn, U.S. Pat. Nos. 3,888,877 ('877) and 4,156,683 ('683), describe synthesis of certain macrocyclic compounds and complexes thereof. Both patents issued from continuations-in-part of U.S. application Ser. No. 43,979, filed June 5, 1970, now abandoned. Example 44 (at column 41 of '877 and column 42 of '683) describes preparation of 5,9-dioxo-1,7-dioxa-4,10-diazacyclododecane (4) by reacting 1,5-diamino-3-oxapentane (3) with diglycolic acid dichloride (2) at specified concentrations and reaction conditions. The product 5,9-dioxo-1,7-dioxa-4,10-diazacyclododecane (4) is reduced to form 1,7-dioxa-4,10-diazacyclododecane (1). ##STR5##
In the above synthesis described by Lehn, diglycolic acid dichloride (2) and 1,5-diamino-3-oxapentane (3) were reacted under high dilution conditions to produce cyclic diamide (4) in 65% yield. The diamide was then reduced with LiAlH.sub.4 to afford diamine 1 in 70% yield.
Cram, et al., "Host-Guest Complexation. 38. Cryptahemispherands and Their Complexes" J. Am. Chem. Soc., Vol. 108, No. 11, 1986, pp. 2989-2998, describe synthesis of 1,7-dioxa-4,10-diazacyclododecane at page 2990. 1,5-diamino-3-oxapentane is reacted with 2,2-oxybis(acetyl chloride) at specified concentrations and reaction conditions. Cram, et al. modified the Lehn procedure and increased the yield of the reduction step to 90%.
Dye, et al., "Flow Synthesis. A Substitute for the High-Dilution Steps in Cryptate Synthesis" J. Org. Chem., Vol. 38, No. 9, 1973, pp 1773-1775, describe synthesis of the macrobicyclic polyoxadiamine ##STR6## according to Dietrich et al., Tetrahedron Lett., 2885, 2889 (1969). Synthesis of intermediates 6 and 7 ##STR7## was done using the high-dilution method described by Stetter and Marx, Justus Liebigs Ann. Chem., Vol. 607, p. 59 (1957). Similar procedures are described by Simmons and Park in J. Amer. Chem. Soc., Vol. 90, 2429, 2431, (1986) in synthesis of diazabicycloalkanes and by Lehn and co-workers (Chem. Commun., 1055, (1970); Tetrahedron Lett. 4557, (1972); J. Chem. Soc., Chem. Commun., 487 (1972); and J. Chem. Soc. Chem. Commun., 1100 (1972)) in synthesis of macrobiocyclic and macrotricyclic ligands.
The procedure used by Dye, et al. requires slow addition with vigorous stirring (over a period of about 8 hours) of dilute (about 0.1M) solutions of the two reagents in benzene into a reaction flask under a nitrogen atmosphere. Dye, et al. found that yields were not greatly reduced by speeding up the addition process, provided that the stirring was sufficiently vigorous.
Fuhrhop and Penzlin, Organic Synthesis, Verlag-Chemie (1984) pp. 222-223 give as an example of a high-dilution method a synthesis originally reported by Lehn for preparing a cryptand using highly diluted 1,8-diamino-3,6-dioxactane and 3,6-dioxaoctanedioyl dichloride in benzene. The reaction sequence is shown below: ##STR8##
The prior art teaches processes for preparing the twelve member diazamonocyclic compound 5,9-dioxo-1,7-dioxa-4,10-diazacyclododecane in small quantities suitable for laboratory experiments; however, such procedure is inappropriate for large scale production of this and similar compounds.
The synthesis of such compounds occurs in a high dilution. The reaction substrates are added at a fixed rate to a comparatively substantially greater volume of solvent, e.g., benzene, over a fixed period of time. The substrates react in the solvent to form the reaction product. In accordance with prior art techniques, to scale up the production of the reaction product, it would be necessary to increase proportionally, the volume of solvent in the reaction to maintain the desired high dilution conditions.
Thus, for example, utilizing the well known Lehn's method for the multigram preparation, one would need about 12 liters of benzene and a suitably sized reactor to produce 66 grams of the cyclic product. By applying the procedure of the present invention, one would only require about 3 liters of the solvent, a smaller reactor and a considerably shorter overall operational time.
Efforts to increase production of the reaction product by increasing concentration of the substrates creates a danger of forming an undesirable linear polymer such as ##STR9## along with the desired reaction product, resulting in lower yield of reaction product and considerable purification effort.
Applicant has discovered that it is possible to continue to add the reaction substrates at predetermined rates to a fixed volume of solvent beyond what would normally be considered possible from the prior art teachings to increase yield of reaction product. The Applicant recognized that the reaction rate of ring closure for a twelve (12) member compound is much faster than that for higher analogs due to fewer degrees of freedom involved in the cyclization step of the smaller twelve (12) member ring. In effect, Applicant is taking advantage of the fact that as the reaction substrates react rapidly to form the reaction product, the concentration of continuously added substrates are held at the low level to maintain the required high dilution conditions.